Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.19 (GABA transaminase)
808 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed prior to 1980 appear to act on sodium channels. gamma-amino butyric acid type A (GABAA) receptors (GABARs) or calcium channels. Benzodiazepines and barbiturates enhance GABAR-mediated inhibition. Phenytion, carbamazepine and possibly sodium valproate decrease high-frequency repetitive firing of action potentials by enhancing sodium channel inactivation. Ethosuximide and sodium valproate reduce a low threshold (T-type) calcium channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin binds to a high affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of gabapentin into neurons; however, this has not been proven and the mechanism of action of gabapentin remains uncertain. Lamotrigine decreases sustained high-frequency repetitive firing of voltage-dependent sodium actin potentials that may result in a preferential decreased release of presynaptic glutamate. Oxcarbazepine's mechanism of action is not known; however, its similarity in structure and clinical efficacy to that of carbamazepine suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underlie the clinical efficacy of vigabatrin. The potential mechanistic bases for rational polypharmacy are reviewed.
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PMID:Is there a mechanistic basis for rational polypharmacy? 929 30

Limbic motor seizures in animals, analogous to complex partial seizures in humans, result in a consistent activation of the mediodorsal thalamus (MD) and, with prolonged seizures, damage to MD. This study examined the functional role of MD in focally evoked limbic motor seizures in the rat. GABA- and glutamate (Glu)-mediated synaptic transmissions in MD were evaluated for an influence on seizures evoked from area tempestas (AT), a discrete epileptogenic site in the rostral piriform cortex. A GABAA receptor agonist, Glu receptor antagonists, or a GABA-elevating agent were focally microinfused into MD before evoking seizures by focal application of bicuculline methiodide into the ipsilateral AT. Focal pretreatment of MD with the GABAA agonist muscimol (190 pmol) protected against seizures evoked from AT. Seizure protection was also obtained with the focal application of 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (500 pmol), an antagonist of the AMPA subtype of Glu receptors, into MD. In contrast, focal pretreatment of MD with a competitive antagonist of the NMDA receptor 2-amino-7-phosphonoheptanoic acid (500 pmol) did not attenuate seizures. The anticonvulsant effects achieved with intra-MD injections of muscimol and NBQX were site-specific, because no seizure protection was obtained with injections placed 2 mm ventral or lateral to MD. Prolonged seizure protection was obtained following GABA elevation in MD after the application of the GABA transaminase inhibitor vigabatrin (194 nmol). These results suggest the following: (1) MD is a critical participant in the generation of seizures elicited focally from piriform cortex; (2) transmission via AMPA receptors, but not NMDA receptors, in MD regulates limbic seizure propagation; and (3) a GABA-mediated system exists within MD, the enhancement of which protects against focally evoked limbic motor seizures.
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PMID:Mediodorsal thalamus plays a critical role in the development of limbic motor seizures. 978 5

Gamma-aminobutyric acid (GABA), a four-carbon non-protein amino acid, is a significant component of the free amino acid pool in most prokaryotic and eukaryotic organisms. In plants, stress initiates a signal-transduction pathway, in which increased cytosolic Ca2+ activates Ca2+/calmodulin-dependent glutamate decarboxylase activity and GABA synthesis. Elevated H+ and substrate levels can also stimulate glutamate decarboxylase activity. GABA accumulation probably is mediated primarily by glutamate decarboxylase. However, more information is needed concerning the control of the catabolic mitochondrial enzymes (GABA transaminase and succinic semialdehyde dehydrogenase) and the intracellular and intercellular transport of GABA. Experimental evidence supports the involvement of GABA synthesis in pH regulation, nitrogen storage, plant development and defence, as well as a compatible osmolyte and an alternative pathway for glutamate utilization. There is a need to identify the genes of enzymes involved in GABA metabolism, and to generate mutants with which to elucidate the physiological function(s) of GABA in plants.
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PMID:Metabolism and functions of gamma-aminobutyric acid. 1052 26

The present study has been aimed to investigate the effect of nitric oxide (NO) on the concentration of gamma-aminobutyric acid (GABA) in rat brain. The concentrations of GABA and glutamate and the activities of glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid transaminase (GABA-T) were determined in groups of animals 5 and 30 min after intraperitoneal injection of a NO-increasing dose (1,000 mg/kg) of its precursor, L-arginine and a dose (50 mg/kg) of N-nitro-L-arginine methyl ester (L-NAME) that inhibits NO synthesis from L-arginine. L-arginine-induced elevation of NO concentration was accompanied by an increased concentration of GABA in the brain. GABA-T activity was inhibited in these animals. NO-decreasing action of L-NAME coincided with a reduction in the concentration of GABA and an enhancement of GABA-T activity. Both L-arginine and L-NAME did not alter the activity of GAD and the concentration of glutamate. An interpretation of these data suggests that NO has a GABA-T-inhibiting role in the brain.
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PMID:A role of nitric oxide as an inhibitor of gamma-aminobutyric acid transaminase in rat brain. 1065 79

Hypoxia may increase GABA levels in neurons by ATP depletion-induced activation of glutamate decarboxylase and by inhibiting GABA transaminase. Hypoglycemia, which also depletes ATP, reduces neuronal levels of GABA and its precursor glutamate. We examined whether differences in glutamate levels may contribute to these altered GABA levels in hippocampal slices. GABA levels were highly correlated with endogenous glutamate levels during both hypoxia and hypoglycemia (R=0.93 for combined data). Hypoxia maximally increased GABA levels (146+/-6.3% of control, S.E.M.) when glutamate remained above 90% of control levels and ATP was at 30% of control levels. Hypoglycemia with similar ATP levels and glutamate levels at 40% of control decreased GABA levels to 55% of control. Effects of inhibitors of glutamate decarboxylase and GABA transaminase suggested that increased synthesis and decreased catabolism may both contribute to increased hypoxic GABA levels. Immunocytochemical studies suggested that hypoxia increased GABA concentrations primarily in neurons and their processes, but not in glial cells. Severe hypoxic ATP depletion increased the release of both GABA and glutamate. Hypoxia increased GABA levels in neurons, while hypoglycemia with a similar severity of ATP depletion decreased GABA levels. Much of the difference may be related to lower levels of precursor glutamate during hypoglycemia. The twofold higher levels of neuroprotective GABA available for release during hypoxia may contribute to differences in the pathophysiology of these metabolic insults.
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PMID:Glutamate dependence of GABA levels in neurons of hypoxic and hypoglycemic rat hippocampal slices. 1072 84

The mechanism of action of the antiepileptic drug lamotrigine has previously been investigated only in acute experiments and is thought to involve inhibition of voltage-dependent sodium channels. However, lamotrigine is effective against more forms of epilepsies than other antiepileptic drugs that also inhibit sodium channels. We investigated whether chronic lamotrigine treatment may affect cerebral amino acid levels. Rats received lamotrigine, 10 mg/kg/day, for 90 days. The hippocampal level of GABA increased 25%, and the activities of glutamate decarboxylase and succinic semialdehyde/GABA transaminase increased 12 and 21% (p< 0.05), respectively, indicating increased GABA turnover. The uptake of GABA and glutamate into proteoliposomes remained unaltered. The level of taurine increased 27% in the hippocampus and 16% in the frontal and parietal cortices. The activities of hexokinase and alpha-ketoglutarate dehydrogenase, remained at control values. Serum lamotrigine was 41.7+/-1.5 microM (mean+/-S.E.M.), which is within the range seen in epileptic patients. Acute experiments with 5, 20 or 100 mg lamotrigine/kg, caused no changes in brain amino acid levels. The results suggest that chronic lamotrigine treatment increases GABAergic activity in the hippocampus. The cerebral increase in taurine, which has neuromodulatory properties, may contribute to the antiepileptic effect of lamotrigine.
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PMID:Chronic lamotrigine treatment increases rat hippocampal GABA shunt activity and elevates cerebral taurine levels. 1116 4

One of the hypotheses in amyotrophic lateral sclerosis (ALS) indicates on excitatory amino acids as the cause of neuronal death. Changes in their concentration in the tissues and body fluids may be the consequence of a defect in their transport, as well as abnormal activities of glutamate metabolizing enzymes. Abnormal synthesis/degradation of these enzymes and/or influence of activators/inhibitors should be taken into account. The activity of enzymes of glutamate metabolism of rat spinal cord in vitro in the presence of serum and cerebrospinal fluid (CSF) of 20 patients with ALS and 20 healthy controls was tested. In the presence of serum of the ALS patients glutaminase was significantly stimulated, instead of being inhibited; the inhibition of GABA aminotransferase, glutamate decaboxylase and aspartate aminotransferase was less evident than in the controls, glutamate dehydrogenase lost its activity more than in control conditions, the inhibition of glutamine synthetase was comparable to that when normal serum was applied. The activity of the enzymes in the presence of CSF of ALS patients was generally similar to that of normal CSF, except of glutaminase which was stimulated and GABA aminotransferase, which was inhibited stronger than in the presence of normal CSF. This study indicates, that changes in glutamate concentration in tissues and body fluids in ALS may be caused, at least partly, by abnormalities in the activity of glutamate metabolism enzymes, which are in turn induced by neurotoxic agents present in body fluids of ALS patients.
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PMID:[Neurotoxic activity of serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients against some enzymes of glutamate metabolism]. 1173 83

Aminooxyacetic acid (AOAA), an inhibitor of gamma-aminobutyric transaminase, stimulates the in vitro GABA release by medial and anterior preoptic hypothalamic areas in prepubertal female rats (6, 15 and 30 days of age). This increase of GABA release at 15 days of age, was accompanied by a significant increase (P<0.01) in the hypothalamic release of glutamate (GLU) and aspartate (ASP), the excitatory amino acids involved in N-methyl-D-aspartate neurotransmission and a decrease in the release of these excitatory amino acids at 6 and 30 days of age (P<0.01). The increase in the hypothalamic release of GLU and ASP at 15 days of age was accompanied by a significant increase of the plasmatic LH and FSH concentration, while the hypothalamic decrease of excitatory amino acids release induced by AOAA also decreased LH and FSH plasmatic levels at 6 and 30 days of age. In summary, the present results show that in female rats there are differences in the effect of GABAergic system the hypothalamic release of GLU and ASP and on gonadotrophin secretion at different ages of prepubertal period, i.e. an inhibitory effect at 6 and 30 days of age and a stimulatory one at 15 days of age. It is proposed that the different effects of GABA on gonadotrophin secretion in prepubertal rats previously described are connected with ontogenic changes in the interrelationships between GABAergic and NMDA neurotransmission systems during sexual maturation of the hypothalamus in female rats. It is probable that these ontogenic modifications are connected with the maturation of interneuronal connection and/or new receptors activity.
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PMID:Ontogenic modifications in the effect of the GABAergic system on the hypothalamic excitatory amino acids: its relationship with GABAergic control of gonadotrophin secretion during sexual maturation in female rats. 1185 59

The growth of the biotrophic pathogen Cladosporium fulvum within the tomato (Lycopersicon esculentum Mill.) leaf is restricted to the intercellular space. Previous studies from this laboratory have demonstrated that gamma-aminobutyric acid (GABA) accumulates to millimolar concentrations in the apoplast during a compatible interaction. We decided to further investigate the role of GABA during infection. A gene encoding a required enzyme for GABA metabolism, GABA transaminase (Gat1), was cloned and sequenced from C. fulvum. The predicted protein sequence of Gat1 had high homology to other fungal GABA transaminases, particularly from Aspergillus nidulans. In vitro expression experiments revealed Gat1 to be strongly expressed during fungal growth on both GABA and glutamate whereas nearly no expression was evident during nitrogen starvation conditions. Expression of Gat1 was also apparent during infection, suggesting for the first time that C. fulvum actively metabolises GABA during infection. This indicates that the fungus may be utilising the GABA in the apoplast as a nutrient source. Further analysis revealed that the expression of tomato glutamate decarboxylase, the enzyme responsible for GABA synthesis, appeared appreciably higher during a compatible interaction than in the incompatible interaction. These findings imply that the infecting fungus may alter the physiology of the tomato leaf with the result that a source of nitrogen is supplied.
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PMID:Evidence that gamma-aminobutyric acid is a major nitrogen source during Cladosporium fulvum infection of tomato. 1185 46

Escherichia coli grows over a wide range of pHs (pH 4.4 to 9.2), and its own metabolism shifts the external pH toward either extreme, depending on available nutrients and electron acceptors. Responses to pH values across the growth range were examined through two-dimensional electrophoresis (2-D gels) of the proteome and through lac gene fusions. Strain W3110 was grown to early log phase in complex broth buffered at pH 4.9, 6.0, 8.0, or 9.1. 2-D gel analysis revealed the pH dependence of 19 proteins not previously known to be pH dependent. At low pH, several acetate-induced proteins were elevated (LuxS, Tpx, and YfiD), whereas acetate-repressed proteins were lowered (Pta, TnaA, DksA, AroK, and MalE). These responses could be mediated by the reuptake of acetate driven by changes in pH. The amplified proton gradient could also be responsible for the acid induction of the tricarboxylic acid (TCA) enzymes SucB and SucC. In addition to the autoinducer LuxS, low pH induced another potential autoinducer component, the LuxH homolog RibB. pH modulated the expression of several periplasmic and outer membrane proteins: acid induced YcdO and YdiY; base induced OmpA, MalE, and YceI; and either acid or base induced OmpX relative to pH 7. Two pH-dependent periplasmic proteins were redox modulators: Tpx (acid-induced) and DsbA (base-induced). The locus alx, induced in extreme base, was identified as ygjT, whose product is a putative membrane-bound redox modulator. The cytoplasmic superoxide stress protein SodB was induced by acid, possibly in response to increased iron solubility. High pH induced amino acid metabolic enzymes (TnaA and CysK) as well as lac fusions to the genes encoding AstD and GabT. These enzymes participate in arginine and glutamate catabolic pathways that channel carbon into acids instead of producing alkaline amines. Overall, these data are consistent with a model in which E. coli modulates multiple transporters and pathways of amino acid consumption so as to minimize the shift of its external pH toward either acidic or alkaline extreme.
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PMID:pH-dependent expression of periplasmic proteins and amino acid catabolism in Escherichia coli. 1210 43


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